Methods for producing an anti-microbial plastic product

ABSTRACT

The invention relates to methods of producing metal-containing antimicrobial plastics or plastic products and also to plastic products obtainable by the method, especially plastic products for medical requirements.

The invention relates to methods of producing metal-containingantimicrobial plastic products and to products obtainable by the method,especially products for medical requirements.

Plastic articles are used in the medical field very frequently and for avery wide variety of purposes. A problem with the use of plasticproducts for medical purposes is the ease with which the plastics can becolonized by microbes. The microbes settle on the surface of the plasticand form a “biofilm”. Infections are a frequent consequence of using aplastic article colonized by microorganisms. It is known that the use ofcatheters and canulas made from plastics may easily result in infectiondue to inward migration of bacteria. Such infections are particularlyserious and common in short-, medium- and long-term central venouscatheters, among others, and also in the urological area, where urethralcatheters and ureteral catheters are routinely used, and in the case ofventicle drain systems. Thus in the Federal Republic of Germany aloneeach day approximately 12 to 15 patients die as a result of infectionsattributable to the use of microbially contaminated catheters.

Numerous attempts have been made to date to prevent the colonization ofplastic articles and, consequently, infections. WO 87/03495 and WO89/04682 describe the impregnation of medical devices and implants withantibiotics. A problem with antibiotic impregnation, however, is thedevelopment and selection of resistant microorganisms.

Another approach to reducing infections associated with the use ofplastic products is the use of metals or metal alloys, e.g., forcatheters (DE 40 41 721, DE 27 20 776 and DE 33 02 567). Of particularsignificance in this context is the antimicrobial property of silver.Silver and its salts, even in traces, exhibit a bacteriostatic andbactericidal action. U.S. Pat. No. 4,054,139 discloses a catheter inwhich for prophylaxis of infection a silver-containing, oligodynamicmaterial has been applied to internal and external surfaces. In theapproaches described, however, it has to date not been possible toachieve satisfactory results in any respect, particularly at thebeginning of use, in respect of sterility with the impregnation ofplastic products.

A method of producing antimicrobial plastic structures with improvedlong-term characteristics is described in WO 01/09229.

In a clinical trial of the catheters described in WO 01/09229 areduction was observed in septic complications by 88% in relation to theinfections caused by conventional catheters. This means that, incomparison to the use of control catheters, where 25 cases of sepsisoccurred, the sepsis cases were reduced to three cases. Accordingly itis indeed the case that the action of a catheter produced by the methoddisclosed in WO 01/09229 is distinctly improved over the state of theart to that date; however, even with the use of the catheters disclosedin WO 01/09229, a colonization rate of 10% is observed, and in that caseas well, moreover, particularly in the first few days followingimplantation of the catheter, there were infections at the entry site ofthe catheter.

Accordingly it has been impossible to date to prevent microbialcontamination of plastic products used medically, particularly ofcatheters, to a satisfactory extent.

The object of the present invention is therefore to provide a method ofproducing plastic products which exhibit satisfactory antimicrobialactivity.

This object is achieved by means of a method of producing anantimicrobial plastic product, comprising

-   A) forming an intermediate product,-   B) treating at least one constituent of the intermediate product    with an antimicrobial metal colloid, and-   C) adding a readily or sparingly soluble salt of an antimicrobial    metal.

Surprisingly the combination of an antimicrobial metal colloid and areadily or, preferably, sparingly soluble salt of an antimicrobial metalproduces a satisfactory antimicrobial activity. In addition to asufficient long-term action, a distinctly improved immediate actionagainst microorganisms as well is achieved with the plastic product ofthe invention. In particular the antimicrobial activity at the beginningis substantially improved as compared with a prior art plastic productas described in WO 01/09229, for example. Thus, in a direct comparisonof the plastic products produced according to WO 01/09229 with theplastic products of the invention, it is possible to show asignificantly higher antimicrobial activity on the part of the plasticproducts of the invention (cf. table 1).

The plastic products according to the present invention, moreover, donot possess increased cytotoxicity as compared with prior art products;a further advantage is that when the plastic products of the inventionare used no thrombogenicity is observed.

Antimicrobial plastic products for the purposes of the invention areproducts which exhibit activity against microorganisms, particularlyagainst bacteria and/or fungi. The action in question may comprise botha bacteriostatic action and a bactericidal action.

By means of the method of the invention it is possible in principle toproduce any desired antimicrobial plastic product, preference beinggiven to producing products which find use in the medical sector. Thesemay be, for example, catheters, hoses, tubes, especially endotrachealtubes, articles used in urology, bone cement, preferably methyl acrylatebone cement, Goretex fabric, toothbrushes, silicone plastics, polymericfilms, textiles, for occupational apparel for example, diapers and/orparts thereof. In one particularly preferred embodiment of the method ofthe invention catheters are produced.

As starting materials for producing the antimicrobial plastic productsof the invention it is possible to employ any desired polymericcompounds which commonly find use in the medical sector. Preferredpolymers are, for example, polyurethanes, polyethylene, polypropylene,crosslinked polysiloxanes, (meth)acrylate-based polymers, cellulose andits derivatives, polycarbonates, ABS, tetrafluoroethylene polymers,polyethylene terephthalates, and the corresponding copolymers.Particular preference is given to the use of polyurethane, polyethyleneand polypropylene and also of polyethylene/polypropylene copolymers,with polyurethane being the most preferred.

In addition to one or more polymeric materials the intermediate productmay comprise further additives. Additives can be, for example, organicor inorganic substances. The intermediate product may comprise anyorganic and inorganic substances which are inert and medicallyunobjectionable, such as, for example, barium sulfate, calcium sulfate,strontium sulfate, titanium dioxide, aluminum oxide, silicon dioxide,zeolites, calcium fluoride (CaF₂), mica, talc, pyrogenic silica, calciumhydroxylapatite, kaolin, zirconium and/or microcellulose. Inorganicsubstances used with preference are barium sulfate, which for certainforms of application can be used simultaneously as an x-ray contrastmedium, and zirconium.

In the method of the invention one or more constituents of theintermediate products are treated with a metal colloid. In this contextit is possible to treat one or more polymeric materials and/or one ormore organic and/or inorganic particles with the metal colloid. Thesupport materials for the metal colloid may be present in theintermediate product in an amount of from about 5 to 50% by weight. Ifbarium sulfate is used as support material it is customarily present inan amount of from about 5 to 30% by weight, with particular preferencein an amount of about 20% by weight. Where silicon dioxide is used assupport material it is present in an amount of from about 30 to 50% byweight, preferably about 40% by weight.

The metal colloid which can be used to treat one or more constituents ofthe intermediate product is suitably prepared by reduction of metal saltsolutions. Where silver is used, it is admixed with a reducing agent,the silver being in the form, for example, of ammoniacal silver nitratesolution. To stabilize the resultant metal colloid it is additionallypossible if desired to use protective substances such as gelatin,silica, starch, dextrin, gum arabic, polyvinyl alcohol or complexingagents such as ethylenediaminetetraacetic acid. It is preferred tooperate without protective substances. Examples of suitable reducingagents are aldehydes (e.g., acetaldehyde), aldoses (e.g., glucose),quinones (e.g., hydroquinone), complex inorganic hydrides (sodium orpotassium boronate), reducing nitrogen compounds (e.g., hydrazine,polyethylenimine), ascorbic acid, tartaric acid and citric acid.

By varying the reducing agents and by varying or omitting thestabilizers it is additionally possible to control the coloring of thecoated support material.

All metals having an antimicrobial action are suitable for the method ofthe invention, such as, for example, silver, copper, gold, zinc,zirconium, bismuth or cerium and also mixtures thereof. Particularpreference is given to silver, which has a high antimicrobial activity.Copper as well is used with preference, and its use advantageouslyachieves activity with respect to fungi as well.

The amount of the metal colloid is advantageously from about 0.1 to 10%,preferably from about 0.5 to 5% by weight.

The application of the metal colloid to one or more constituents of theintermediate product can take place either in one step or can befollowed by drying and repeated a number of times. Both techniques canbe used to achieve a very high metal concentration. By varying thereducing agents and by varying or omitting the stabilizers it ispossible to control the particle size of the metal. If silver is used asthe metal colloid, the preferred particle size is in the range from 10to 50 nm. Silver of this particle size is referred to as nanosilver. Inone preferred embodiment the addition of the reducing agent and thedeposition of the nanosilver is followed by the precipitation, byaddition of phosphoric acid, of the silver that has remained in thesolution, the precipitated silver being in the form of silver phosphate,which is referred to below as “silver phosphate in the nascent state”and is distinguished by particularly rapid onset of the antimicrobialaction.

The amount of the metal colloid is chosen so that a sufficient portionof the surface of the plastic product is composed of metal particles inorder to achieve an antimicrobial activity.

In accordance with the invention a readily soluble or sparingly solublesalt of an antimicrobial metal is additionally added to the intermediateproduct. This salt preferably comprises a silver salt, zinc salt, coppersalt, cerium salt, platinum salt, zirconium salt, bismuth salt and/orgold salt and also mixtures thereof. Particular preference is given tousing a silver salt, especially silver sulfate and/or silver phosphatein the nascent state. In principle suitability is possessed by anyreadily or sparingly soluble salts of antimicrobially active metals thatare stable to exposure to light and are physiologically unobjectionable.The amount of the metal salt used can be from 0.1 to 5% by weight, basedon the total weight of the intermediate product, preferably from 0.5 to1% by weight.

After the constituents of the intermediate product at least partlytreated with a metal colloid have been mixed with the sparingly solublemetal salt, the mixture obtained is processed further to give a plasticproduct. This can be done, for example, by extruding, injection molding,mixing, kneading or (hot) pressing. Preferred shaping processes areextrusion and injection molding.

The present invention further provides plastic products obtainable bythe method of the invention. The plastic products in question arepreferably products which find use in the medical sector. In oneparticularly preferred embodiment the method of the invention is used toproduce catheters.

Examples of the preferred medical products are venous catheters forshort-term implantation, where not only the outside of the catheter butalso each lumen inside, the Luer lock and the manifold are made of thematerial obtained in accordance with the invention. Experiments haveshown that an inoculum size of 10⁹ microbes, used to contaminate thesurface, is eliminated completely within less than 9 hours. Additionallythere are peripheral venous canulas, Sheldon catheters for implantationover 6 weeks for hemodialysis, Hickman-type catheters for long-termimplantation, with a cuff made from material produced in accordance withthe invention (antimicrobial activity of at least one year ascertained),port catheters, where at least the port chamber is made from materialproduced in accordance with the invention, and advantageously all otherconstituents thereof, ventricular drain catheters (minimum period ofactivity 3 years), bladder catheters, cystostomy, nephrostomy catheters,urether stents (e.g., of polyurethane or silicone base material;advantageously the entire urine collection system and the connectors arecomposed of said material), thorax drains and the attached suctionsystem, endotracheal tubes, Tenckhof catheters with cuff, bone cements(based on methyl acrylate, for example), toothbrushes (bristles andhandle), surgical suture material, filament material for producingantimicrobial textiles, coating materials for antimicrobial coating,e.g., of hoses for ventilation, antimicrobial wound coverings anddressings in the event of burn injuries.

In the text below a description is given of preferred embodiments of themethod of the invention.

In one preferred embodiment polyurethane pellets with a size ofapproximately 1 mm³ are used as polymeric material. A furtherconstituent of the intermediate product is barium sulfate, whichfunctions as support material. Deposited on the barium sulfate are about3 to 10% by weight, or even more if desired, of nanosilver. Theintermediate product additionally includes about 0.5 to 1% by weight ofsilver sulfate or silver phosphate, particularly in the nascent state.The constituents of the intermediate product are mixed; furtherprocessing can take place by extrusion.

In another preferred embodiment the metal salt used comprises acombination of silver and copper in a silver/copper ratio of about 2:1.This combination advantageously also possesses a satisfactory microbialactivity against fungi.

According to another preferred embodiment a combination of a metalcolloid, with particular preference nanosilver, and zirconium silicateis used. Particularly suitable are silver to zirconium silicate weightratios of 1:1-10.

The invention is further illustrated by the figures and examples below.

FIGS. 1 to 3 show results of experiments relating to antimicrobialactivity. The microorganism used was in each case Staphylococcusepidermidis ATCC 14 990, with a starting microbe count of 5×10⁷ CFU/ml.

In the experiment shown in FIG. 1, 0.8% of nanosilver and 0.5% of silversulfate were used.

In the experiment shown in FIG. 2, 0.8% of nanosilver and 1.0% of silversulfate were used.

FIG. 3 shows an experiment in which 0.8% of nanosilver and no additionalsilver sulfate was used.

EXAMPLES Comparative Example 1 Commercially Customary Plastic Accordingto WO 01/09299

A: Preparation of a Silver Colloid

1.0 g (5.88 mmol) of AgNO₃ p.a. are dissolved in 100 ml of distilledwater and the solution is admixed with 1.0 ml (14.71 mmol) of 25%strength aqueous NH₃. To prepare the silver colloid, a solution of 258.7mg (5.88 mmol, 330 μl) of acetaldehyde in 50 ml of distilled water isadded slowly dropwise to the first solution over a period of 30 minutesat 40° C.

B: Coating of Polyurethane Pellets

10 minutes after the end of the dropwise addition as described inexample 1 about 50 g of polyurethane pellets of Tecothane TT-1085A areadded and for coating with colloidal silver are stirred vigorously at40° C. for 2 hours to start with and then at room temperature for 3hours. The silver colloid is separated off by rapid filtration through afluted filter of appropriate pore size, and the pellets are washed againwith the filtrate and, while still moist, are transferred to anevaporation boat. After the removal of excess silver colloid solution,not adhering to the polymer, drying takes place at 70° C. for 10 hours.

Example 2 Plastic with Improved Antimicrobial Activity

A: Adsorption of Colloidal Silver on Barium Sulfate

The following are dissolved in succession in 360 ml of distilled waterat 50° C.: 0.6 g of gelatin and 6.0 g of AgNO₃. 7.8 ml of 25% strengthaqueous ammonia solution are added to the first solution. With vigorousstirring at 50° C. a solution of 3.18 g of anhydrous glucose in solutionin 120 ml of distilled water is metered in slowly. When approximatelyhalf the amount of glucose has been added dropwise, 100 g of bariumsulfate is introduced with vigorous stirring into the silver colloidalready formed, and the addition of glucose is continued. When theaddition of glucose is at an end the suspension is agitated with aturbine stirrer for a further 2 hours, initially at 50° C., andthereafter at 70° C. for 3 hours.

Subsequently the solid is separated from the liquid by filtration orcentrifugation. The solid is washed repeatedly with ultra-pure wateruntil free of electrolyte, and is filtered, dried at 70° C. to 80° C.and finely comminuted.

B: Admixing of Silver Sulfate

The dried and comminuted barium sulfate is admixed with 2.5% by weightor 5% by weight of finely ground silver sulfate and the two componentsare mixed thoroughly.

C: Mixing of the Individual Constituents

20% by weight of the coated barium sulfate/silver sulfate mixture aremixed thoroughly with 77.6% by weight of polyurethane pellets and 2.4%by weight of a further, inorganic, uncoated material, e.g., titaniumdioxide, and the mixture is subjected to a further operation, e.g., anextrusion.

If 2.5% by weight of silver sulfate are added in step B, the plastic setout under A in table 1 is obtained; if 5% by weight of silver sulfateare added in step B, the plastic set out under B in table 1 is obtained.

Example 3 Plastic with Improved Antimicrobial Activity

A: Adsorption of Colloidal Silver on Barium Sulfate

18 g of AgNO₃ are dissolved in 1080 ml of distilled water at 50° C. and200 g of barium sulfate are added. The suspension is stirred vigorouslyfor about 20 minutes and thereafter is admixed with 23.4 ml of 25%strength aqueous ammonia solution.

With continual stirring, and with the temperature remaining the same,9.6 g of anhydrous glucose in solution in 360 ml are slowly addeddropwise. After the end of the addition of glucose, the procedurecontinues in the same way as in example 2A up to the point of thegrinding of the dried barium sulfate.

B: Admixing of Silver Sulfate

The admixing of silver sulfate takes place in the same way as in example2B.

C: Mixing of the Individual Constituents

In the same way as in example 2 the barium sulfate mixture of silversulfate is mixed with the other constituents and subjected to furtherprocessing.

Example 4 Determination of the Antimicrobial Activity

The antimicrobial activity of the plastics of the invention wasdetermined by incubating samples of the plastics in question with atrypcase-soy broth nutrient solution containing different microbes at37° C.

Microorganisms Used:

Staphylococcus epidermidis (S. epidermidis) ATCC 14 990, S. epidermidis,fresh clinical isolate from a patient with catheter-associated sepsis,

Staphylococcus aureus (S. aureus) ATCC 25923,

Escherichia coli (E. coli), fresh clinical isolate from a patient withcatheter associated sepsis,

Pseudomonas aeruginosa (P. aeruginosa), fresh clinical isolate from apatient with catheter-associated sepsis.

The microbe count was adjusted in a photometer either to 5×10⁷ colonyforming units (CFU)/ml (corresponding in the case of Staphylococci to anOD of 0.30 at 457 nm, in the case of P. aeruginosa and E. coli to an ODof 0.65) or 10⁹ CFU/ml (OD 0.65 for staphylococci at 475 nm, 1.2 for P.aeruginosa and E. coli). Determination of the CFU/ml was carried out inparallel by serial dilution on agar plates, and the microbe countsdetermined by photometric measurement were confirmed.

Plastic Materials:

Polyurethane (Tecoflex) was used, a material from which virtually allimplantable central venous catheters are manufactured. This material wascoextruded with nanosilver (particle size 3 to 5 nm) in an amount of0.8% or 1.3% by weight and with different concentrations of silversulfate (0.25%, 0.5%, 0.75% and 1.0%). Extrudates with an externaldiameter of 1.6 mm were manufactured. From these extrudates, pelletseach 1 mm in length were chopped, with 10 pellets giving a surface areaof approximately 1 cm² and 50 pellets a surface area of 5 cm².

Test Method:

The sections of plastic (with a surface area of either 1 cm² or 5 cm⁵)were introduced into a suspension containing either 5×10⁷ CFU/ml or 10⁹CFU/ml of the above-described microbes in physiological saline solution.The test specimens were shaken at a speed of 120 rotations/minute. Atthe beginning of the investigation (starting microbe count) and after 6,12, (18), 24, 36 and (48) hours in each case 1 loop (2 μl) was removedand plated out on agar (Müller Hinton agar). The plates were incubatedat 37° C. for 24 hours. Subsequently the microbe count on the agar platewas determined by counting the colonies.

All of the experiments were repeated three times, with the data belowrepresenting in each case the mean values of the three correspondingexperiments.

Results:

Table 1 below lists the colony counts found for the test experiment, asobtained with S. epidermidis ATCC 14 990. TABLE 1 Time in hours 0 6 1224 36 48 A 0.8% nanosilver, 0.5% silver sulfate 5 × 10⁷ CFU/ml 1 cm²* 5× 10⁷ 2 × 10³ 10³ 0 0 — 5 cm² 5 × 10⁷ 10³ 0 0 0 — 10⁹ CFU 1 cm² 10⁹ 10⁷0 0 0 — 5 cm² 10⁹ 10⁵ 0 0 0 — B 0.8% nanosilver, 1.0% silver sulfate 5 ×10⁷ CFU/ml 1 cm² 5 × 10⁷ 10⁴ 0 0 0 — 5 cm² 5 × 10⁷ 10³ 0 0 0 — 10⁹ CFU 1cm² 10⁹ 10⁶ 10² 0 0 — 5 cm²** 10⁹ 10⁴ 0 0 0 — C 0.8 nanosilver(commercially customary plastic according to WO 01/09229; Medex) 5 × 10⁷CFU/ml 1 cm² 5 × 10⁷ 10⁷ 10⁶ 10⁴ 10³ 0 5 cm² 5 × 10⁷ 10⁶ 10⁵ 10³ 10² 010⁹ CFU 1 cm² 10⁹ 10⁹ 10⁹ 10⁹ 10⁹ 10⁸⁺ 5 cm²*** 10⁹ 10⁹ 10⁹ 10⁹ 10⁹ 10⁶⁺*weak growth of the colonies after 48 hours' incubationshown in FIG. 1shown in FIG. 2shown in FIG. 3

A corresponding growth behavior is also shown by the wild strain of S.epidermidis, S. aureus ATCC 25923, and E. coli and P. aeruginosa. Thetest experiments showed that the addition of silver sulfatesignificantly increases the immediate antimicrobial activity (comparisonof A or B with C). The increase in the activity as a result of addingsilver sulfate is dose-dependent, but an activity can be observed evenwith an addition of 0.5% of silver sulfate. The plastic of the inventionexhibits a significantly improved antimicrobial activity in comparisonwith a plastic containing only nanosilver (experiment C). In the case ofthe prior art plastic tested (from WO 01/09229) sterility can beobserved only after 48 hours with a starting microbe count of 5×10⁷ ofCFU/ml. With a starting microbe count of 10⁹ CFU/ml there is still weakgrowth of the colonies even after 48 hours.

Example 5

Investigation of Support Material Containing Zirconium Silicate

The barium sulfate support material is admixed in a first series ofexperiments with 20% by weight of zirconium silicate, in a second seriesof experiments with 20% by weight of nanosilver and 20% by weight ofzirconium silicate. The resulting mixtures are admixed with differentquantities of microbes and then the microbial growth is recorded over 48hours. Zirconium silicate without Zirconium silicate with silver -microbe nanosilver - microbe count/ml count/ml Time 10⁹ 10⁸ 10⁷ 10⁶ 10⁹10⁸ 10⁷ 10⁶  2 h + + + − + +/− − −  3 h + + + − + +/− − −  6 h + + +/−− + − − − 12 h + +/− − − + − − − 18 h + +/− − − + − − − 24 h + − − − + −− − 30 h + − − − + − − − 36 h + − − − + − − − 42 h + − − − +/− − − − 48h + − − − − − − −+ = growth− = sterile+/− = no growth but also still not sterile

Example 6

Comparative Investigation of the Antimicrobial Activity of ZirconiumSilicate on Barium Sulfate as Support Alone or with Nanosilver Time (h)1 2 3 4 6 9 12 Control (microbe count/ml) 10⁹ 10⁹ 10⁹ 10⁹ 10⁹ 10⁹ 10⁹ 1%zirconium silicate on barium 10⁹ 10⁸ 10⁸ 10⁷ 10⁷ 10⁶ 10⁵ sulphate 0.1%zirconium silicate on barium 10⁹ 10⁹ 10⁹ 10⁹ 10⁹ 10⁹ 10⁹ sulphate 1%zirconium silicate + 5% 10⁸ 10⁶ — — — — — nanosilver on barium sulfate0.1% zirconium silicate + 5% 10⁹ 10⁷ 10⁵ — — — — nanosilver on bariumsulfate 1% zirconium silicate + 3.5% 10⁹ 10⁸ 10⁶ — — — — nanosilver onBaSO₄ 0.1% zirconium silicate + 3.5% 10⁹ 10⁹ 10⁷ 10⁶ 10⁶ 10⁵ —nanosilver on barium sulfate

Example 7

Investigation of the Antimicrobial Activity when Using Nanosilver andSilver Phosphate in the Nascent State on Barium Sulfate Support (3.6%Ag; 5% Silver Phosphate

Adsorption of colloidal silver on barium sulfate and generation ofultrafinely divided silver phosphate in the nascent state

14.45 g of silver nitrate are dissolved in 360 ml of distilled water at50° C. and then with vigorous stirring 100 g of barium sulfate areintroduced. The suspension is stirred for about 20 minutes. Thereafter19.3 ml of a 25% strength aqueous ammonia solution are added.

With continual stirring and with the temperature remaining the same, asolution of 5.25 g of glucose monohydrate in 182 ml of distilled wateris metered slowly into the suspension. After the end of the addition ofglucose stirring is continued for 2 to 4 hours more at 50° C. andfinally the nonreduced silver still present is precipitated with about50 ml of 0.1 molar phosphoric acid and the suspension is brought to a pHof approximately 6.

Stirring is continued until the suspension has cooled to roomtemperature. Subsequently the solid is separated off by sedimentation,filtration or centrifugation.

The resulting solid is washed repeatedly with ultrapure water until freeof electrolyte and finally is dried at 70 to 80° C. in a drying cabinetand, if desired, is comminuted after drying.

The product produced in this way is whitish gray in color; itscomposition is 3.6% nanosilver, 5% silver phosphate on BaSO₄. Themicrobe count at a concentration of 1% or 0.1% was determined inaccordance with example 4: Time (h) 1 2 3 1% 10⁷ 10⁵ 0.1 10⁸ 10⁷ 10⁶

Example 8

A: Adsorption of Colloidal Silver on Barium Sulfate

9 g of silver nitrate are dissolved in 360 ml of distilled water heatedto 50° C., and with vigorous stirring 100 g of barium sulfate areintroduced. After 20 minutes of stirring 12 ml of a 25% strength ammoniasolution are added.

Subsequently, with the temperature remaining the same, a solution of5.25 g of glucose monohydrate in 182 ml of distilled water is metered inslowly. After the end of the addition of glucose the suspension isstirred at 50° C. for a further 2 to 4 hours and then at 70° C. for 1 to3 hours.

After complete reaction the solid is separated from the aqueous phaseand washed repeatedly with ultrapure water or distilled water until freeof electrolyte. The washed solid is dried at 70 to 80° C. in a dryingcabinet and thereafter comminuted to the primary particle size.

B: Admixing of Silver Phosphate

The desired amount (1 to 5% by weight) of ultrapure silver phosphate isadded to the solid obtained according to A and the two components aremixed thoroughly. Investigation as described in example 4 gave resultsof a similarly good quality to those shown in example 7.

1. A method of producing an antimicrobial plastic product, comprising A)forming an intermediate product, B) treating at least one constituent ofthe intermediate product with an antimicrobial colloidal metal, and C)adding a readily or sparingly soluble salt of an antimicrobial metal. 2.The method of claim 18, characterized in that the sparingly solublemetal salt is selected from the group consisting of silver salts, zincsalts, copper salts, cerium salts, zirconium salts, bismuth salts,platinum salts and/or gold salts.
 3. The method of claim 2,characterized in that the metal salt comprises silver sulfate and/orsilver phosphate.
 4. The method of claim 3, characterized in that themetal salt is present in an amount of from 0.1 to 1.0% by weight, basedon the total weight of the intermediate product.
 5. The method of claim2, characterized in that the metal salt is present in a silver/copperratio of approximately 2:1.
 6. The method of claim 1, characterized inthat the intermediate product comprises one or more polymeric materials.7. The method of claim 6, characterized in that the intermediate productcomprises polyurethane.
 8. The method of claim 6, characterized in thatthe intermediate product comprises further additives.
 9. The method ofclaim 8, characterized in that the additives comprise organic and/orinorganic particles.
 10. The method of claim 9, characterized in thatthe organic and/or inorganic particles are selected from the groupconsisting of barium sulfate, calcium sulfate, strontium sulfate,titanium dioxide, aluminum oxide, silicon dioxide, zeolites, calciumfluoride (CaF₂), mica, talc, pyrogenic silica, calcium hydroxylapatite,kaolin and/or microcellulose.
 11. The method of claim 8, characterizedin that the additives comprise inorganic particles that comprise bariumsulfate and/or pyrogenic silica.
 12. The method of claim 9,characterized in that the polymeric materials and inorganic particlesare treated with a colloidal metal.
 13. The method of claim 1,characterized in that the constituent of the intermediate product thatis inorganic particles are treated with a colloidal metal comprisesinorganic particles.
 14. The method of claim 1, characterized in thatthe colloidal metal comprises colloidal silver.
 15. The method of claim1, characterized in that the mixture of treated intermediate product andsparingly soluble metal salt is shaped by extruding, injection molding,mixing, kneading or (hot) pressing.
 16. A plastic product made by theprocess of claim
 1. 17. The plastic product of claim 16 in the form of acatheter.
 18. The method of claim 1, characterized in that the metalsalt is a sparingly soluble salt of an antimicrobial metal.
 19. Themethod of claim 1, characterized in that the colloidal metal isnanosilver, and metal salt is zirconium silicate.
 20. The method ofclaim 19, characterized in that the silver to zirconium silicate weightratio is 1:1-10.